[Metabolomic interference induced by short-chain chlorinated paraffins in human normal hepatic cells].

Short-chain chlorinated paraffins (SCCPs) are an emerging class of persistent organic pollutants (POPs) that are widely detected in environmental matrices and human samples. Because of their environmental persistence, long-range transport potential, bioaccumulation potential, and biotoxicity, SCCPs pose a significant threat to human health. In this study, metabolomics technology was applied to reveal the metabolomic interference in human normal hepatic (L02) cells after exposure to low (1 µg/L), moderate (10 µg/L), and high (100 µg/L) doses of SCCPs. Principal component analysis (PCA) and metabolic effect level index (MELI) values showed that all three SCCP doses caused notable metabolic perturbations in L02 cells. A total of 72 metabolites that were annotated by MS/MS and matched with the experimental spectra in the Human Metabolome Database (HMDB) or validated by commercially available standards were selected as differential metabolites (DMs) across all groups. The low-dose exposure group shared 33 and 36 DMs with the moderate- and high-dose exposure groups, respectively. The moderate-dose exposure group shared 46 DMs with the high-dose exposure group. In addition, 33 DMs were shared among the three exposure groups. Among the 72 DMs, 9, 9, and 45 metabolites participated in the amino acid, nucleotide, and lipid metabolism pathways, respectively. The results of pathway enrichment analysis showed that the most relevant metabolic pathways affected by SCCPs were the lipid metabolism, fatty acid ß-oxidation, and nucleotide metabolism pathways, and that compared with low-dose exposure, moderate- and high-dose SCCP exposures caused more notable perturbations of these metabolic pathways in L02 cells. Exposure to SCCPs perturbed glycerophospholipid and sphingolipid metabolism. Significant alterations in the levels of phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins indicated SCCP-induced biomembrane damage. SCCPs inhibited fatty acid ß-oxidation by decreasing the levels of short- and medium-chain acylcarnitines in L02 cells, indicating that the energy supplied by fatty acid oxidation was reduced in these cells. Furthermore, compared with low- and moderate-dose SCCPs, high-dose SCCPs produced a significantly stronger inhibition of fatty acid ß-oxidation. In addition, SCCPs perturbed nucleotide metabolism. The higher hypoxanthine levels observed in L02 cells after SCCP exposures indicate that SCCPs may induce several adverse effects, including hypoxia, reactive oxygen species production, and mutagenesis in L02 cells.

Integrated metabolomics and network pharmacology revealing the mechanism of arsenic-induced hepatotoxicity in mice.

Endemic arsenic (As) poisoning is a severe biogeochemical disease that endangers human health. Epidemiological investigations and animal experiments have confirmed the damaging effects of As on the liver, but there is an urgent need to investigate the underlying mechanisms. This study adopted a metabolomic approach using UHPLC-QE/MS to identify the different metabolites and metabolic mechanisms associated with As-induced hepatotoxicity in mice. A network pharmacology approach was applied to predict the potential target of As-induced hepatotoxicity. The predicted targets of differential metabolites were subjected to a deep matching for elucidating the integration mechanisms. The results demonstrate that the levels of ALT and AST in plasma significantly increased in mice after As exposure. In addition, the liver tissue showed disorganized liver lobules, lax cytoplasm and inflammatory cell infiltration. Metabolomic analysis revealed that As exposure caused disturbance to 40 and 75 potential differential metabolites in plasma and liver, respectively. Further investigation led to discovering five vital metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis and nicotinate and nicotinamide metabolism pathways. These pathways may responded to As-induced hepatotoxicity primarily through lipid metabolism, apoptosis, and deoxyribonucleic acid damage. The network pharmacology suggested that As could induce hepatotoxicity in mice by acting on targets including Hsp90aa1, Akt2, Egfr, and Tnf, which regulate PI3K Akt, HIF-1, MAPK, and TNF signaling pathways. Finally, the integrated metabolomics and network pharmacology revealed eight key targets associated with As-induced hepatoxicity, namely DNMT1, MAOB, PARP1, MAOA, EPHX2, ANPEP, XDH, and ADA. The results also suggest that nicotinic acid and nicotinamide metabolisms may be involved in As-induced hepatotoxicity. This research identified the metabolites, targets, and mechanisms of As-induced hepatotoxicity, offering meaningful insights and establishing the groundwork for developing antidotes for widespread As poisoning.

BushenHuoxue decoction suppresses M1 macrophage polarization and prevents LPS induced inflammatory bone loss by activating AMPK pathway.

Abnormal bone metabolism and subsequence osteoporotic fractures are common complications of chronic inflammatory diseases. No effective treatment for these bone-related complications is available at present. The chronic inflammatory state in these diseases has been considered as a key factor of bone loss. Therefore, the combination of inflammation inhibition and bone loss suppression may be an important strategy for reducing bone damage associated with inflammatory diseases. Bushen Huoxue Decoction (BSHXD) is a traditional Chinese herbal compound that has demonstrated the ability to improve bone quality and increase bone density. However, the efficacy of BSHXD on inflammatory bone loss and its underlying mechanisms remain unclear. This study aimed to investigate whether BSHXD inhibits inflammatory bone loss in mice and its potential molecular mechanisms. In the present study, the effect of BSHXD on lipopolysaccharide (LPS)-induced M1 polarization of RAW264.7 macrophage and on local inflammatory bone loss model of mouse skull was determined. The results showed that after treating RAW264.7 cells with LPS for 24 h, the expression levels of IL-1ß (39.42 ± 3.076 ng/L, p < 0.05), IL-6 (49.24 ± 1.766 mg/L, p < 0.05) and TNF-α (286.3 ± 27.12 ng/L, p < 0.05) were significantly increased. The addition of BSHXD decreased the expression levels of IL-1ß, IL-6, and TNF-α to 31.55 ± 1.296 ng/L, 37.94 ± 0.8869 mg/L, and 196.4 ± 25.25 ng/L, respectively (p < 0.05). The results of immunofluorescence staining, Western blotting (WB) and flow cytometry indicated that the proportion of M1 macrophages in RAW264.7 cells treated with BSHXD for 24 h was significantly lower than that in the LPS group (13.36% ± 0.9829% VS 24.80% ± 4.619%, p < 0.05). The evidence from in-vitro experiments showed that the immunomodulatory ability of BSHXD may be associated with the activation of AMP-dependent protein kinase (AMPK) pathway in LPS-treated macrophages. In addition, the results of micro-CT, H&E staining, immunohistochemical staining and immunofluorescence staining of mouse skull further demonstrated that BSHXD treatment significantly alleviated LPS-induced local bone loss and inflammatory damage in mouse skull model. All results indicated that BSHXD significantly inhibited inflammatory factors release and M1 polarization of macrophage through AMPK signaling pathway. Therefore, BSHXD may be a promising drug for the treatment of inflammatory bone loss.

Paeoniflorin Ameliorates Hyperprolactinemia-Induced Inhibition of Osteoblastogenesis by Suppressing the NF-κB Signaling Pathway.

Hyperprolactinemia is a common endocrine disease in women of reproductive age. Research has shown that patients with hyperprolactinemia often have decreased bone mineral density and an increased risk of fractures. However, there is still a lack of effective treatments. Paeoniflorin, one of the primary bioactive components in peony, is widely used in traditional Chinese medicine. Research has shown that paeoniflorin promotes osteoblast differentiation. However, whether paeoniflorin plays a role in hyperprolactinemia-induced osteoblastogenesis inhibition is not yet clear. In this study, we investigated the effect of paeoniflorin on prolactin (PRL)-mediated inhibition of osteoblast function. Our results showed that prolactin significantly reduced the expression of alkaline phosphatase (ALP), Osterix, and runt-related transcription factor 2 (RUNX2) in MC3T3-E1 cells cultured in an osteoblast differentiation medium, suggesting that prolactin inhibited osteoblast function. After treatment with paeoniflorin (PF), the expression of these osteoblast markers was upregulated. In addition, our findings proved that paeoniflorin increased the absorbance values of ALP-positive cells and the areas of alizarin red S (ARS) deposition compared to those in the prolactin group, suggesting that paeoniflorin reversed the PRL-induced reduction in osteoblast differentiation. The PRL-induced activation of nuclear factor kappa B (NF-κB) was significantly reversed by paeoniflorin, indicating that paeoniflorin promoted osteoblast function by inhibiting the NF-κB signaling pathway. In summary, these results showed that paeoniflorin alleviated the inhibitory effect of prolactin on osteoblastogenesis by suppressing the NF-κB signaling pathway.

An integrated transcriptomic and proteomic approach to dynamically study the mechanism of pollen-pistil interactions during jasmine crossing.

Jasmine (Jasminum sambac Aiton, Oleaceae) flowers are widely consumed in many countries for their tea-making, medicinal and ornamental properties. To improve the quality and yield of flowers, it is very important to carry out cross-breeding between different petal types of jasmine. However, because of the difficulty of sexual reproduction, there is no report on the success of jasmine crosses. In this paper, single- and double-petal jasmine plants were crossed artificially. The stigmas of single-petal plants post pollination, including those at 0 h after pollination (CK), 1 h after pollination (T1) and 6 h after pollination (T2), were sequenced by transcriptomic combined with proteomic analyses. A total of 178,098 gene products were assembled. Simultaneously, a total of 2337 protein species were identified. Some regulatory gene products and functional protein species were identified that may be involved in the process of pollen-pistil interactions. These findings suggest that the identified differentially expressed gene products and differentially accumulated protein species may play vital roles in jasmine plants in response to pollen-pistil interactions, providing important genetic resources for further functional dissection of the molecular mechanisms of these interactions. SIGNIFICANCE: These results have important scientific significance to take effective measures to overcome pre-fertilization barriers and to guide the cross breeding of jasmine. Further, they can also be used for reference in other plant breeding with the same fertilization barriers.

Plasma glycerophospholipid profile, erythrocyte n-3 PUFAs, and metabolic syndrome incidence: a prospective study in Chinese men and women.

BACKGROUND: Animal studies have highlighted critical roles of glycerophospholipid (GP) metabolism in various metabolic syndrome (MetS)-related features such as dyslipidemia, obesity, and insulin resistance. However, human prospective studies of associations between circulating GPs and risks of MetS are scarce. OBJECTIVES: We aimed to investigate whether GPs are associated with incidence of MetS in a well-established cohort. METHODS: A total of 1243 community-dwelling Chinese aged 50-70 y without MetS at baseline and followed up for 6 y were included in current analyses. A total of 145 plasma GPs were quantified by high-throughput targeted lipidomics. MetS was defined using the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. RESULTS: After 6 y, 429 participants developed MetS. Eleven GPs, especially those with long-chain polyunsaturated fatty acids (LCPUFAs) or very-long-chain polyunsaturated fatty acids (VLCPUFAs) at the sn-2 position, including 1 phosphatidylcholine (PC) [PC(18:0/22:6)], 9 phosphatidylethanolamines (PEs) [PE(16:0/22:6), PE(18:0/14:0), PE(18:0/18:1), PE(18:0/18:2), PE(18:0/20:3), PE(18:0/22:5), PE(18:0/22:6), PE(18:1/22:6), and PE(18:2/22:6)], and 1 phosphatidylserine (PS) [PS(18:0/18:0)], were positively associated with incident MetS (RRs: 1.16-1.30 per SD change; Bonferroni-corrected P < 0.05). In network analysis, the strongest positive association for MetS incidence was evidenced in a module mainly composed of PEs containing C22:6 and PSs [RR: 1.21; 95% CI: 1.12, 1.31 per SD change; Bonferroni-corrected P < 0.05]. This association was more pronounced in participants with lower erythrocyte total n-3 PUFA concentrations [Bonferroni-corrected Pinter(P value for the interaction)< 0.05]. CONCLUSIONS: Elevated plasma concentrations of GPs, especially PEs with LCPUFAs or VLCPUFAs at the sn-2 position, are associated with higher risk of incident MetS. Future studies are merited to confirm our findings.

Polyphosphazene-Based Drug Self-Framed Delivery System as a Universal Intelligent Platform for Combination Therapy against Multidrug-Resistant Tumors.

Combination therapy is a burgeoning research field due to the advantages of the synergistic contributions from incorporating drugs and promising potentials in the therapy of aggressive tumors with multidrug resistance (MDR). Given the great efforts, it is extremely difficult to coordinate pharmacokinetics between drugs and elucidate the mechanism of synergistic effects. Additionally, limited by the inherent solubility of anticancer drugs, a common strategy for simultaneously delivering various drugs is yet a challenging target. To overcome these, we develop a drug self-framed delivery system (DSFDS) via treating multiple drugs as monomers to constructing cyclomatrix polyphosphazene nanoparticles (CPPZ NPs). Notably, it is a superflexible common platform to realize the rational design of combination therapy, which is verified by delivering doxorubicin (DOX) with mitoxantrone (Mit), resveratrol (RES), curcumin (Cur), and porphyrin (TPP). As a proof of concept, DOX-RES-CysM-CPPZ NP was selected to evaluate the therapeutic feasibility of DSFDSs. Obvious improvement in killing MDR tumors indicated an efficient combination therapy. The corresponding synergistic mechanism of DOX and RES was also addressed in this work. Throughout cutting-edge research, the drug self-framed delivery system is drawing promising blueprint for combination therapy.

Oxygen therapy in patients with retinal artery occlusion: A meta-analysis.

BACKGROUND: Oxygen therapy has been widely used for RAO (retinal artery occlusion) patients; however, inconsistent results have been reported. METHODS: PubMed, Web of Science, EMBASE, Medline (OvidSP), Cochrane, China National Knowledge Infrastructure (CNKI), and Wanfang Database were examined. The primary endpoint was visual acuity (VA), and RevMan software 5.3 was used to statistically analyze the outcomes. RESULTS: Seven randomized controlled trials (RCTs) met the inclusion criteria. Patients who received oxygen therapy exhibited probability of visual improvement about 5.61 times compared with the control group who did not receive oxygen therapy (OR = 5.61; 95% CI, 3.60-8.73; p < 0.01). No statistically significant difference was observed between oxygen inhalation methods (Chi2 = 0.18, df = 1, p = 0.67), combined therapy (Chi2 = 0.21, df = 1, p = 0.64), or RAO type (Chi2 = 0.06, df = 1, p = 0.81). Conversely, 100% oxygen (Chi2 = 4.55, df = 1, p < 0.05) and hyperbaric oxygen (Chi2 = 4.55, df = 1, p < 0.05) significantly improved VA in RAO patients. Better effect was showed in period within 3 months (Chi2 = 5.76, df = 1, p < 0.05). The most effective treatment length was over 9 hours (Chi2 = 6.58, df = 1, p < 0.05). CONCLUSION: Oxygen therapy demonstrated beneficial effects in improving VA in RAO patients, particularly when patients were treated with 100% hyperbaric oxygen and for over 9 hours.

n-Butanol extract from Folium isatidis inhibits lipopolysaccharide-induced inflammatory cytokine production in macrophages and protects mice against lipopolysaccharide-induced endotoxic shock.

Sepsis, which is caused by severe infection, is an important cause of mortality, but effective clinical treatment against sepsis is extremely limited. As the main component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) plays a major role in inflammatory responses. Studies have shown beneficial pharmacological effects for Folium isatidis. The present study further illuminated the effects of n-butanol extract from Folium isatidis in LPS-induced septic shock and identified the main active chemical components. Our study showed that pretreatment with n-butanol extract from Folium isatidis not only significantly inhibited LPS-induced tumor necrosis factor-α and interleukin-6 production but also markedly and dose dependently enhanced the recruitment of MyD88, the phosphorylation of extracellular signal-regulated kinase, and the degradation of IκB-α. Additionally, the extract exhibited dramatic protective effects against lung injury and death in mice with septic shock. Eight main active compounds were identified, including organic acids, glycoside, indolinones, and flavonoids. These findings provide a perspective on the respiratory protection offered by n-butanol extract from Folium isatidis in LPS-induced sepsis and outline a novel therapeutic strategy for the treatment of sepsis.

Chinese Herb Astragalus membranaceus Enhances Recovery of Hemorrhagic Stroke: Double-Blind, Placebo-Controlled, Randomized Study.

We tested the effect of Astragalus membranaceus (AM) on acute hemorrhagic stroke. Seventy-eight patients were randomly assigned to Group A (3 g of AM three times/day for 14 days); or Group B (3 g of placebo herb). A total of 68 patients (Group A 36, Group B 32) completed the trial. The increase of functional independence measure scale score between baseline and week 4 was 24.53 ± 23.40, and between baseline and week 12 was 34.69 ± 28.89, in the Group A was greater than 11.97 ± 11.48 and 23.94 ± 14.8 in the Group B (both P≦0.05). The increase of Glasgow outcome scale score between baseline and week 12 was 0.75 ± 0.77 in the Group A was greater than 0.41 ± 0.50 in the Group B (P < 0.05). The results are preliminary and need a larger study to assess the efficacy of AM after stroke.